APOL1 variants: Understanding the basis of disparities in rates of kidney disease

总结 超过50万美国人患有终末期肾病（ESRD）。非裔美国人发展肾脏 失败率比欧洲美国人高4-5倍。最近，我们发现了两个编码序列， 载脂蛋白L1（APOL 1）变异体在这一重大健康差异中占很大比例。APOL1 肾脏疾病变体对多种不同类型的肾脏疾病有重大影响，包括 高血压相关ESRD、局灶节段性肾小球硬化（FSGS）和HIV相关肾病 （艾滋病毒）。风险遗传是隐性的：具有两个变异APOL 1等位基因的个体的风险增加7-30倍。 肾脏疾病的风险。我们预测，超过350万非洲裔美国人有高风险APOL 1， 基因型两个风险等位基因的存在并不会导致所有个体的肾脏疾病，这表明， 其他遗传和环境因素也是重要的调节因素。理解为什么有些人 高风险基因型发生肾脏疾病而其他基因型不发生，这将改善风险分层， 最适合治疗的途径。因此，我们建议：目标1：确定更多的遗传 APOL 1基因位点的修饰物。我们的数据表明，APOL 1肾脏疾病风险变异是获得性的， 功能等位基因由于并非所有具有两个风险等位基因的个体都会发生疾病，因此其他局部多态性可能 调节APOL 1的表达，调节致病性APOL 1编码突变的作用。我们将 定义可能改变APOL 1基因表达的结构变异，并测试它们对细胞凋亡率的影响。 两个致病等位基因我们将检测转录因子和microRNA结合的多态性是否 位点影响这些APOL 1风险等位基因的多态性。目的2：寻找APOL 1的上位修饰物 外显率APOL 1肾脏风险变异在非洲的频率增加，至少部分原因是， 提供了对锥虫的保护。我们假设额外的遗传位点同时 选择保护免受肾损伤的主要编码风险等位基因， 这些位点在与欧洲人混合后可能已经减少。在这里，我们将进行全基因组筛选， 对于可能防止或加重APOL 1变体诱导的肾损伤的多态性。我们将确定 与野生型和编码变体ApoL 1差异结合的蛋白质，因为这些结合配偶体可以调节 风险变量造成的伤害。目的3：鉴定APOL 1介导的肾细胞凋亡的生化修饰剂 疾病ApoL 1肾病风险变异体在其他风险因素的情况下可能是最有害的。 在这里，我们探讨了两个重要因素如何与APOL 1基因型相互作用，导致肾脏疾病。 维生素D被认为是对肾损伤的保护，而某些脂质分布可能会促进损伤。我们 询问这些分子是否在体外改变APOL 1生物学，以及这些介质的生化水平是否 预测具有APOL 1风险基因型的个体可能发展为肾病。

SUMMARY More than 500,000 Americans suffer from end-stage renal disease (ESRD). African Americans develop kidney failure at rates 4-5 fold higher than European Americans. Recently, we discovered two coding sequence variants in ApolipoproteinL1 (APOL1) that account for a large proportion of this major health disparity. APOL1 kidney disease variants have a major impact on multiple different types of kidney disease including hypertension-associated ESRD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Risk inheritance is recessive: individuals with two variant APOL1 alleles have a 7-30 fold increased risk for kidney disease. We predict that more than 3.5 million African Americans have the high risk APOL1 genotype. The presence of two risk alleles does not lead to kidney disease in all individuals, indicating that other genetic and environmental factors are important modifiers. Understanding why some individuals with the high-risk genotype develop kidney disease while others do not will improve risk stratification and may illuminate the pathways most amenable to therapy. We therefore propose to: Aim 1: Identify additional genetic modifiers at the APOL1 gene locus. Our data suggest that APOL1 kidney disease risk variants are gain-of- function alleles. Since not all individuals with two risk alleles develop disease, other local polymorphisms may regulate expression of APOL1, modulating the effect of the disease-causing APOL1 coding mutations. We will define structural variants that may alter APOL1 gene expression, and test their effects on the penetrance of the two disease-causing alleles. We will test whether polymorphisms in transcription factor and microRNA binding sites affect the penetrance of these APOL1 risk alleles. Aim 2: Find epistatic modifiers of APOL1 penetrance. The APOL1 renal risk variants increased in frequency in Africa, at least in part, because they provided protection against trypanosomes. We hypothesize that additional genetic loci were simultaneously selected that protect against renal injury from the major coding risk alleles, and that the protective effect of these loci may have diminished after admixture with Europeans. Here, we will perform a genome-wide screen for polymorphisms that may protect against or exacerbate APOL1 variant-induced renal injury. We will identify proteins that bind differentially to wild type and coding variant ApoL1, as these binding partners may modulate injury caused by the risk variants. Aim 3: Identify biochemical modifiers of APOL1-mediated renal disease. ApoL1 kidney disease risk variants may be most deleterious in the setting of additional risk factors. Here, we explore how two important factors may interact with APOL1 genotype to cause renal disease. Vitamin D is believed to be protective against renal injury, while certain lipid profiles may promote injury. We ask whether these molecules alter APOL1 biology in vitro, and whether biochemical levels of these mediators predict which individuals with the APOL1 risk genotype are likely to develop kidney disease.